Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner

Gong, Yiyi; Wang, Caihong; Jiang, Yi; Zhang, Shaosen; Shi, Feng; Fu, Yan; Luo, Yongzhang

doi:10.3390/cells9010144

Cited by 15 publications

(13 citation statements)

References 58 publications

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“…Mouse monoclonal antibody against human Hsp90α was developed by our laboratory whose specificity and efficiency were verified [ 11 , 25 ]. Recombinant human Hsp90α protein was provided by Protgen (Yantai, China) [ 58 , 65 ]. Antibodies against LYVE-1 (ab14917), LRP1 (ab28320), CXCL8 (ab110727) and β-actin (ab8227) were from Abcam (Cambridge, UK).…”

Section: Methodsmentioning

confidence: 99%

Extracellular Hsp90α Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer

Hou

Chen

et al. 2021

IJMS

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Early detection and discovery of new therapeutic targets are urgently needed to improve the breast cancer treatment outcome. Here we conducted an official clinical trial with cross-validation to corroborate human plasma Hsp90α as a novel breast cancer biomarker. Importantly, similar results were noticed in detecting early-stage breast cancer patients. Additionally, levels of plasma Hsp90α in breast cancer patients were gradually elevated as their clinical stages of regional lymph nodes advanced. In orthotopic breast cancer mouse models, administrating with recombinant Hsp90α protein increased both the primary tumor lymphatic vessel density and sentinel lymph node metastasis by 2 and 10 times, respectively. What is more, Hsp90α neutralizing antibody treatment approximately reduced 70% of lymphatic vessel density and 90% of sentinel lymph node metastasis. In the in vitro study, we demonstrated the role of extracellular Hsp90α (eHsp90α) as a pro-lymphangiogenic factor, which significantly enhanced migration and tube formation abilities of lymphatic endothelial cells (LECs). Mechanistically, eHsp90α signaled to the AKT pathway through low-density lipoprotein receptor-related protein 1 (LRP1) to upregulate the expression and secretion of CXCL8 in the lymphangiogenic process. Collectively, this study proves that plasma Hsp90α serves as an auxiliary diagnosis biomarker and eHsp90α as a molecular mediator promoting lymphangiogenesis in breast cancer.

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Section: Methodsmentioning

confidence: 99%

Extracellular Hsp90α Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer

Hou

Chen

et al. 2021

IJMS

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“…Studying breast cancer-derived cell lines, Stivarou et al found that extracellular HSP90 was overexpressed in mammosphere-forming cell cultures, while the mammospheres were enriched with CSC-like CD44(+)/CD24(−/low) cells; the authors suggested that extracellular HSP90 represents a phenotypic marker of breast CSCs [106]. It was recently reported that the secretion of HSP90 by breast CSCs is required for cancer-related signaling pathways and breast tumor xenograft growth in mice [109]; inhibiting the HSP90 secretion and/or extracellular HSP90 functions was therefore suggested as a potential approach to CSC-based therapy of cancer.…”

Section: Extracellular Hsp90mentioning

confidence: 99%

“…As for the latter, the inhibition of HSP90 secretion from CSCs by means of multifunctional magnetic nanoparticles (MNPs) seems to be a very promising approach because this MNP-exerted effect was accompanied by sensitization of CSCs to thermotherapy and chemotherapy [107]. Gong et al have shown that metformin, a drug against type 2 diabetes, can suppress such an EMT/cancer stemness-associated phenomenon as metastasis occurrence by inhibiting HSP90α secretion in a phosphorylation-dependent manner involving AMP-activated protein kinase α1 and protein kinase Cγ [109].…”

Section: Targeting Extracellular Hsp90mentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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“…In addition, metformin augmented Foxo3a nuclear localization and protein stabilization to active Foxo3a with IKKβ repression and MDM2 phosphorylation involvement, leading to the level of E-cad increase [42]. For protein kinase Cγ (PKCγ), which was attenuated after AMPK-α1 phosphorylation, it modulated Hs90α activation [48].…”

Section: Discussionmentioning

confidence: 99%

Metformin May Block the Way Breast Cancer Metastasis: A Meta-analysis and Mechanism Review

Yang¹,

Wang²,

Zhang³

et al. 2020

Preprint

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Background Metformin, which is cheap and easy to get, is a first-line anti-hyperglycemia drug. Recently, its anti-tumor effect has been revealed. Here we performed a meta-analysis to summarize previous studies and a narrative review to gather the mechanisms involved in the potential relationship. Methods We searched related articles in database of Pubmed, EMbase, Web of science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), the Wanfang and Sinomed and obtained 8 clinic trials that investigated the connection between metformin and breast cancer metastasis, containing 2 randomized controlled trials (RCTs) and 6 retrospective cohort studies. We evaluated each retrospective cohort study by Newcastle-Ottawa Scale (NOS), while RCT by Chcorane Risk of Bias tool. Pooled hazard ratios (HRs), risk ratios (RRs) and we calculated associated 95% confidence intervals (CIs) with a random-effect, generic inverse variance method. We also collected the possible mechanisms of cancer metastasis inhibition from metformin. Results A total of 8 studies containing 13919 breast cancer patients without distant metastasis before they got anticancer treatment. The result showed that adjuvant metformin in treatment of local breast cancer facilitated to suppress metastasis (HR = 0.69, 95% CI = 0.57–0.82, p < 0.0001, I2 = 0%), and the result was consistent with the subgroup of breast cancer patients with type 2 diabetes mellitus (T2DM) (HR = 0.68, 95% CI = 0.57–0.82, p < 0.0001, I2 = 0%). Conclusion The meta-analysis suggested metformin might repress the metastasis and be benefit to distant metastasis-free survival (DMFS) when added to systemic breast cancer therapy, supporting anti-tumor effects of metformin on breast cancer.

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Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner

Cited by 15 publications

References 58 publications

Extracellular Hsp90α Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer

Extracellular Hsp90α Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Metformin May Block the Way Breast Cancer Metastasis: A Meta-analysis and Mechanism Review

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